title: A negative genetic interaction map in isogenic cancer cell lines reveals cancer cell vulnerabilities.
abstract: Improved efforts are necessary to define the functional product of cancer mutations currently being revealed through large-scale sequencing efforts. Using genome-scale pooled shRNA screening technology, we mapped negative genetic interactions across a set of isogenic cancer cell lines and confirmed hundreds of these interactions in orthogonal co-culture competition assays to generate a high-confidence genetic interaction network of differentially essential or differential essentiality (DiE) genes. The network uncovered examples of conserved genetic interactions, densely connected functional modules derived from comparative genomics with model systems data, functions for uncharacterized genes in the human genome and targetable vulnerabilities. Finally, we demonstrate a general applicability of DiE gene signatures in determining genetic dependencies of other non-isogenic cancer cell lines. For example, the PTEN(-/-) DiE genes reveal a signature that can preferentially classify PTEN-dependent genotypes across a series of non-isogenic cell lines derived from the breast, pancreas and ovarian cancers. Our reference network suggests that many cancer vulnerabilities remain to be discovered through systematic derivation of a network of differentially essential genes in an isogenic cancer cell model.
authors.affiliation: 1] Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario, Canada [2] Saskatchewan Cancer Agency, Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Franco J
authors.initials: FJ
authors.lastname: Vizeacoumar
authors.forename: Roland
authors.initials: R
authors.lastname: Arnold
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Vizeacoumar
authors.forename: Megha
authors.initials: M
authors.lastname: Chandrashekhar
authors.forename: Alla
authors.initials: A
authors.lastname: Buzina
authors.forename: Jordan T F
authors.initials: JT
authors.lastname: Young
authors.forename: Julian H M
authors.initials: JH
authors.lastname: Kwan
authors.forename: Azin
authors.initials: A
authors.lastname: Sayad
authors.forename: Patricia
authors.initials: P
authors.lastname: Mero
authors.forename: Steffen
authors.initials: S
authors.lastname: Lawo
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Tanaka
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Brown
authors.forename: Anastasia
authors.initials: A
authors.lastname: Baryshnikova
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Mak
authors.forename: Yaroslav
authors.initials: Y
authors.lastname: Fedyshyn
authors.forename: Yadong
authors.initials: Y
authors.lastname: Wang
authors.forename: Glauber C
authors.initials: GC
authors.lastname: Brito
authors.forename: Dahlia
authors.initials: D
authors.lastname: Kasimer
authors.forename: Taras
authors.initials: T
authors.lastname: Makhnevych
authors.forename: Troy
authors.initials: T
authors.lastname: Ketela
authors.forename: Alessandro
authors.initials: A
authors.lastname: Datti
authors.forename: Mohan
authors.initials: M
authors.lastname: Babu
authors.forename: Andrew
authors.initials: A
authors.lastname: Emili
authors.forename: Laurence
authors.initials: L
authors.lastname: Pelletier
authors.forename: Jeff
authors.initials: J
authors.lastname: Wrana
authors.forename: Zev
authors.initials: Z
authors.lastname: Wainberg
authors.forename: Philip M
authors.initials: PM
authors.lastname: Kim
authors.forename: Robert
authors.initials: R
authors.lastname: Rottapel
authors.forename: Catherine A
authors.initials: CA
authors.lastname: O'Brien
authors.forename: Brenda
authors.initials: B
authors.lastname: Andrews
authors.forename: Charles
authors.initials: C
authors.lastname: Boone
authors.forename: Jason
authors.initials: J
authors.lastname: Moffat
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D004843:Epistasis, Genetic; D005260:Female; D053263:Gene Regulatory Networks; D020043:Genes, Essential; D015894:Genome, Human; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human